Like father, like worm

Darwin is often considered the father of evolution. In school, we’re usually taught that Darwin got it right with his theory of evolution. We’re also told that Lamarck was basically wrong, and we associate him with the “crazy” idea of the inheritance of acquired traits. You know, the story about giraffes stretching their necks to reach food on tall trees and then passing their longer necks on to their offspring. So according to what we learn, Darwin is the genius, and Lamarck is the loser. But… are they really?

It turns out both were brilliant. And, actually, Lamarck wasn’t the only one proposing the inheritance of acquired traits: it was a shared assumption at the time. He mentioned it in his work, but it was not a distinctive insight of his theory, and he didn’t believe in it more strongly than Darwin did. So it makes no sense to make such a distinction between Darwin and Lamarck because they both accepted the idea. The real difference is that Darwin made crucial contributions with his ideas of natural selection, variation, and adaptation to environmental pressures. But Lamarck also had important insights, like the gradual transformation of species and the influence of the environment on an organism’s form.

So why is Lamarck still associated with the inheritance of acquired traits? The reason is historical. Later Darwin’s followers, the neo-Darwinists of the 19th and 20th centuries, wanted to separate their new, selection-based theories from the older “soft inheritance” ideas. They needed someone to represent that outdated way of thinking, and Lamarck became the perfect symbol. That’s how the label “Lamarckian” came to mean anything related to the inheritance of acquired traits.

But setting Darwin and Lamarck aside for a moment, what if the idea of inherited acquired traits wasn’t completely wrong after all? Today, modern biologists, especially those studying epigenetics, are finding that the environment can influence heredity. This is called transgenerational inheritance. I spoke with one of the leading researchers in this field, Professor Oded Rechavi from Tel Aviv University. For the past ten years, his lab in the Department of Neurobiology has been challenging one of biology’s core dogmas, showing that acquired traits can indeed be inherited through mechanisms involving small RNA molecules. He received several distinctions, including the Schmidt Science Polymath Award, the Blavatnik Award, the Kadar Award, the Krill Wolf Award, the Alon and F.I.R.S.T (Bikura) Prizes, and the Gross Lipper Fellowship.

Juan García Ruiz: What is your research about?

Oded Rechavi: We study many different things, but our main focus is on transgenerational epigenetic inheritance, which is the kind of inheritance that happens independently of changes in the DNA sequence. Most people know DNA as the material that carries hereditary information, but in some organisms, inheritance can also involve other molecules like RNA. This kind of inheritance follows different rules than DNA-based inheritance and allows for some fascinating phenomena, the most interesting being the inheritance of acquired traits. In other words, changes that happen during an individual’s lifetime can somehow be passed on to the next generations.

JGR: Is this related somehow to epigenetics?

OR: People use the word epigenetics in different ways. Personally, I define it as any inheritance that occurs across cell divisions or across generations without changes to the DNA sequence itself. There are several mechanisms that make this possible: chemical modifications to the DNA, changes in chromatin structure (like histone methylation), or inheritance through RNA molecules. Some people even include prions when they talk about epigenetics.

JGR: How does this happen mechanistically in case of RNA epigenetics?

OR: First, an important disclaimer: everything I describe applies to our studies with these simple worms called C.elegans. Time will tell whether this is also true in other organisms. We expect that it might be, but we are not certain yet.

In these worms, people identified a mechanism called RNA interference (RNAi) by which small RNA molecules regulate gene expression by silencing specific genes. This turned out to be conserved in other organisms like humans. So when I talk about RNA inheritance, I am talking about RNA molecules that can regulate gene expression also in next generations through this same process.

For molecules to be inheritable, they need to have a way to amplify themselves. DNA can replicate because each strand serves as a template to make the complementary one, and that’s how genetic information is passed on. In the case of RNA, there are enzymes called RNA-dependent RNA polymerases that use RNA itself as a template to make more RNA. Without this amplification, the RNA signal would fade over time, becoming weaker in each generation. But what we see is that these RNA responses can actually persist across multiple generations.

JGR: Does this mean that the production of these RNA molecules in the ancestors need to occur in the sex cells to be transmitted to the next generations?

OR: The interesting thing, and one of the reasons small RNAs are so fascinating, is that in C. elegans (and some other organisms), these molecules can actually move between cells (Chen & Rechavi, 2021). They can travel from somatic cells to the germ cells that produce the next generation. So small RNAs can be made in any tissue, and they will eventually reach the germline and be passed on. These organisms even have dedicated mechanisms that ensure this transfer happens.

JGR: For how many generations can RNA-based information be transmitted?

OR: When worms are exposed to different stressors, you can observe epigenetically transmitted responses that persist for 3 to 5 generations at the population level. However, at the individual level, some worms can carry this information across hundreds of generations. We have identified genes that regulate how long these inherited responses last; we call them motek genes, an acronym for MOdified Transgenerational Epigenetic Kinetics. In mutants that are defective in motek genes, we observe that at the population level they all inherit RNAs for hundreds of generations. They are genes that encode for proteins that act like a clock, limiting how long the inheritance persists.

The basic idea behind the motek genes is that worms seem to “expect” that their offspring will live in a similar environment, but not indefinitely. Generally, if you keep worms in the same environment for multiple generations, the inherited response will last longer.

JGR: At the individual level, how can worms “decide” what will become an adaptive transgenerational response? How is it ensured that RNA is produced in a way that makes it stable enough to be passed on to the offspring?

OR: There are a few possibilities for when a transgenerational response can actually be adaptive. If the environment experienced by the parents matches that of their offspring, then the inherited response is obviously beneficial. But there are also cases where the parental response turns out to be disadvantageous for the next generation because the environments don’t match. So, really, all possibilities are on the table.

To better understand this, we performed some evolution experiments in the lab. We found that when worms are grown at high temperatures, this changes the pool of small RNAs (sRNAs) in their sperm and harms sperm function in their offspring. Because these worms are hermaphrodites (they produce both sperm and eggs), having defective sperm means they can’t fertilize themselves. In response, they secrete a hormone that attracts males, leading them to mate with others instead (Toker et al., 2022).

Mating increases genetic variability since it mixes genomes. Once that happens, the resulting genetic change becomes encoded in DNA — a more stable and long-lasting modification. So this is one way that short-term transgenerational RNA responses can lead to more permanent evolutionary changes, even within just a few generations.

JGR: You usually focus on challenging triggers like starvation or antiviral responses. Has this mechanism also been observed in non-challenging traits, which aren’t protective per se, but still provide some kind of advantage?

OR: There’s a really interesting paper showing that you can actually teach a worm to prefer a particular odor, and that this preference can then be passed on to the next generation. That study came out before small RNA inheritance became a big topic. You could imagine that a similar mechanism might be at play there, but it still needs to be studied in detail.

JGR: What have been your main findings in the field of transgenerational transmission?

OR: In my postdoc I showed that challenging worms with viruses produce transgenerational responses. It was the first time that inherited small RNAs were sequenced, and also the first time that we showed that these RNA-dependent RNA polymerases, the enzymes that amplify small RNAs, play a role in RNA inheritance. It was already known that these enzymes amplified RNA, but not their role in inheritance. Later on, we also showed for the first time that exposing worms to challenging environments could lead to transgenerational changes in their offspring’s physiology.

In addition, we discovered genes that control how long these inherited effects last: the motek genes (Houri-Ze’evi et al., 2016). We found that there are specific rules that determine how these responses are passed on across generations and among different worm lineages, explaining why some worms inherit a lot of small RNAs, while others don’t.

More recently, we’ve shown that producing small RNAs just in the brain of a worm is enough to trigger transgenerational changes (Posner et al., 2019). This opens up the possibility that brain activity could influence the next generation, something that hasn’t been demonstrated before. When we alter the levels of small RNAs specifically in the brain, it affects not only RNA inheritance but also the offspring’s behavior. For example, modifying small RNA production in the parental brain changes how efficiently their descendants can find food.

Finally, I’d mention the evolutionary experiment I talked about earlier: when worms are grown at hitgh temperatures, it alters their behavior in the next generations about whether to mate or not. This has direct evolutionary consequences because it increases genome diversity.

JGR: I have a provocative question. Why is studying worm physiology important for society?

OR: I’m very interested in worms, but not because I’m a zoologist. The thing is, about four out of every five animals on this planet are worms, numerically speaking. So if we understand something fundamental about worms, we’re learning something about life in general. So even if all our findings turned out to apply only to worms, I’d be happy. But of course I’d even happier if it also applied to other organisms, including humans. This is something we still don’t know.

If this kind of inheritance also happens in humans, the implications would be huge. This would mean that when we talk about heredity, we shouldn’t just focus on DNA sequences, but also consider RNA.

Beyond that, our work is driven mostly by curiosity, and we try to challenge different dogmas, things people say “can’t happen”. For example, it was believed that it was impossible to inherit acquired traits, but our research shows that this is not entirely true. So, as an exercise in creativity and in rethinking the limits of biology, I think this kind of work really matters.

JGR: What are the frontiers of the field of transgenerational inheritance? What are the black boxes?

OR: The biggest questions are: does this kind of inheritance affect evolution? And if so, how? What are the barriers to small RNA inheritance? Does it happen in other organisms, and if it does, are the same mechanisms at play?

JGR: What do you like most about doing research? What did you write in your cover letters to explain how you fell in love with science?

OR: Being a scientist is kind of a loophole. We often joke about the downsides of academia, but honestly, there are so many advantages. We get to follow our curiosity and have direct control over what we do. We can be creative, even if that creativity has to operate within certain constraints. Our environment is constantly changing, and we get to work with smart, curious people all the time. We set our own schedules and enjoy an unparalleled level of freedom in our work. I don’t think I’d trade it for any other job. Well, maybe for being an NBA player.

JGR: Do you remember any advice from another scientist that had a big impact on you?

OR: I actually remember bad advice (laughs). A lot of young investigators tend to be very cautious. They don’t want to hire too many people or take big risks early on. I think that’s a mistake. But the good advice I got was to “just go for it” from the start. Don’t wait until you are super established to take chances. You never know what’s going to work. Even projects that seem safe might fail. So it’s better to give everything from the beginning. That energy and commitment will give you the motivation to keep going.

JGR: Do you think we’ll ever change the way we publish scientific research?

OR: Yes, I do. I think the current situation is only temporary. A short phase in the long history of publishing. In fact, I am building a platform for changing the situation which is called q.e.d (qedscience.com) to do something about it. I really believe that this model where you wait for years for peer review, only to get rejected and start all over again, won’t last forever. q.e.d is an AI that gives you the feedback you need, and we built it to speed publication and to change the entire landscape of academic publishing.

I think we’ll move toward publishing preprints, and journals and editors will act more like curators, selecting the most interesting papers and highlighting them. q.e.d will offer readers another dimension helping them understand and judge what they read critically. Each journal might even develop its own approach. In the future, I imagine scientists will simply upload their papers online in whatever form they like, and the community, owing in part to critical AI services, will decide what deserves attention.

JGR: Do you have a book recommendation?

OR: Yes, a few actually. It’s not exactly a science book, and it’s a bit controversial, but it’s related to transgenerational inheritance. It’s an excellent book called The Case of the Midwife Toad by Arthur Koestler, about a rather infamous scientist named Paul Kammerer. Another great one is The Common Thread by John Sulston. It’s about the race to sequence the human genome, and it’s really fantastic. And of course, there’s the classic What Is Life? by Erwin Schrödinger.

References